Lung cancer remains the major cancer-related cause of death in the Western World and intense efforts are directed toward the development of adjuvant therapy for the treatment of this disease. While immunotherapy targeting the adaptive immune response in the form of T lymphocytes has been successful for several solid tumors, such as melanoma and prostate cancer, it has been extremely unsuccessful in lung cancer. We have recently discovered that, unlike other solid tumors, the innate rather than adaptive immune system plays a critical role in immunosurveillance for lung cancer. Furthermore, individual differences in natural killer cells (NK cells) play a role in susceptibility or resistance to this disease. In this proposal we focus on the role of natural killer cells in immunosurveillance and immunotherapy of lung cancer. We plan to explore mechanistic aspects of lung cancer immunosurveillance in a mouse model and will evaluate the immunologic basis of human susceptibility to this disease. In the first aim we will study the role of the activating receptor NKp46 in lung cancer-specific activation of NK cells. In the second aim we will evaluate the mechanisms used by NK cells to control lung cancer in vivo and in the third aim we will focus on the inhibitory receptor Ly49C as it relates to strain-specific differences in anti-cancer activity of NK cells. In the fourth and final aim we plan to evaluate the licensing status of human NK cells and susceptibility to lung cancer. 1